Alex Dean

Osteoporosis drug (WAY-316606) may help with hair loss?

Blog Post created by Alex Dean on May 15, 2018

The skeletal system is one of the largest organs in the human body, and the maintenance of healthy and strong bones is critical to good health and quality of life. The incidence of bone disease and fractures continues to rise, especially in our aging population. Osteoporosis is a bone disease predominately affecting postmenopausal women. This disease disrupts the balance in bone formation and resorption, the later of which predominates, resulting in the catabolic loss of trabecular bone mass and structure. Traditional therapies have involved anticatabolic agents, targeting osteoclasts that are responsible for bone resorption. These agents arrest the resorptive process and minimize further loss in bone mass, however, bone mass that has been lost is not restored. To restore catabolized bone, an anabolic agent is often necessary to regain bone integrity and structure. Currently, the only anabolic agent approved by the FDA for the treatment of chronic osteoporosis is Teriparatide, a truncated synthetic peptide of the natural human parathyroid hormone (hPTHa).

The signaling processes invoked by PTH treatment and responsible for the subsequent anabolic effects on bone are not completely understood. Recently, the anabolic action of PTH on bone has been linked to the modulation of the Wnt signaling pathway in osteoblasts (OB). The Wnt signaling pathway, activated by secreted Wnt glycoproteins, regulate various biological processes, including skeletal development. The Wnt/-Catenin canonical signaling pathway is activated by the binding of Wnt to a membrane receptor complex composed of a frizzled (Fzd) GPCR and a low-density lipoprotein receptor-related protein (LRP). The binding results in a signaling cascade, leading to the stabilization of β-catenin, translocation to the nucleus, and activation of transcriptional factors. The Wnt signaling process is regulated by many factors, including extracellular components such as WIF-1, Dkk-1, SOST, and secreted frizzled-related protein-1 (sFRP-1 or SARP-2). Human sFRP-1 is a 35 kD protein consisting of 313 amino acids and containing 2 distinct structural domains, a netrin domain, and a cysteine-rich domain (CRD). The later domain is homologous to the Fzd receptor. sFRP-1 is thought to interact with Wnt via the CRD domain in a competitive manner with the Fzd receptor. Thus sFRP-1 is a negative regulator or an antagonist of the Wnt signaling pathway. Increased expression of sFRP-1 in OB cells results in suppression of Wnt signaling, leading to decreased OB survival, activation, and differentiation. Conversely, deletion of the sFRP-1 gene in mice results in increased Wnt signaling, leading to OB activation, proliferation, and differentiation resulting in increases in trabecular bone.

The canonical Wnt/β-catenin pathway plays a crucial role in modulating multiple cellular processes, such as cell survival, proliferation, differentiation, and oncogenesis. Secreted frizzled-related protein 1 (SFRP1), mapped to chromosome 8p12-p11.1, has become a research focus in recent years, as it can negatively regulate Wnt signaling. SFRP1 possesses a cysteine-rich domain that binds and then sequesters Wnts away from active receptor complexes. Besides, SFRP1 can antagonize Wnt signaling by forming a Wnt signaling inhibitory complex with frizzled receptors. In recent years, down regulation or inactivation of SFRP1 has been reported in various types of malignant tumors, including prostate, gastric, breast, ovarian, and bladder cancers. Using a Kaplan-Meier analysis, one study revealed that GBM patients with positive SFRP1 expression had a significantly longer overall survival time relative to those with negative SFRP1 expression.

Hair loss is a common disorder and can lead to psychological distress. Cyclosporine A, a fungal metabolite commonly used as an immunosuppressant, can potently induce hair growth in humans. However, it cannot be effectively used to restore hair growth because of its toxic profile. The current pharmacological treatment for hair loss disorders is unsatisfactory, with patients being limited to only two FDA-approved hair growth promoters (minoxidil and finasteride), neither of which is robustly and universally efficacious. Given the severe psychological burden and negative quality of life that can be associated with hair loss, additional, but safe, human hair growth-promoting agents are urgently needed.

There are relatively few known drugs that cause excessive hair growth (hypertrichosis) in patients. Among these, the immunosuppressive calcineurin inhibitor, Cyclosporine A (CsA), most frequently and characteristically induces hypertrichosis. CsA also prolongs active hair growth (anagen) in organ-cultured human scalp hair follicles (HFs) ex vivo. Likely, the hair growth-stimulatory effects of CsA are independent of its T cell-inhibitory activity, because human HFs grafted onto immunocompromised nude mice treated with CsA also show anagen prolongation in vivo.

Taken together, the data introduce SFRP1 as a physiologically important regulator of canonical β-catenin activity in a human (mini-)organ, the HF. The researchers also present the first evidence that the SFRP1 inhibitor, WAY-316606, effectively enhances β-catenin activity in mammalian skin cell populations, namely in both human hair pre-cortex keratinocytes and DP fibroblasts ex vivo.

References:

Moore, W. J., Kern, J. C., Bhat, R., Commons, T. J., Fukayama, S., Goljer, I., … & Stauffer, B. (2008). Modulation of Wnt signaling through inhibition of secreted frizzled-related protein I (sFRP-1) with N-substituted piperidinyl diphenylsulfonyl sulfonamides. Journal of medicinal chemistry, 52(1), 105-116.

Hawkshaw, N. J., Hardman, J. A., Haslam, I. S., Shahmalak, A., Gilhar, A., Lim, X., & Paus, R. (2018). Identifying novel strategies for treating human hair loss disorders: Cyclosporine A suppresses the Wnt inhibitor, SFRP1, in the dermal papilla of human scalp hair follicles. PLOS Biology, 16(5), e2003705.

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